The objectives of this project are to support the goals of the Undiagnosed Diseases Program by creating a sequencing core facility to provide exome and genome sequencing for the network. The extramural opportunity Clinical Sites for an Undiagnosed Diseases Network will create a consortium of institutions that will build common protocols to improve patient access to state-of-the-art diagnostic methods, and to promote discovery and innovation in diagnosing and treating these patients. Important to this coordinated effort is the use of common diagnostic modalities such that data can be readily shared among the sites. Therefore the designation of a single sequencing core facility that will provide state-o-the-art exome and genome sequencing for the network has been proposed. The Baylor Whole Genome Laboratory (WGL) is a collaborative effort of the Human Genome Sequencing Center and the Department of Molecular and Human Genetics at Baylor, which merges the specific expertise of both areas. The WGL is a CAP and CLIA certified laboratory that developed exome sequencing as its first test. Since the beginning of the clinical exome sequencing service in October 2011, the WGL has sequenced, analyzed, and provided final clinical reports of exome sequencing for over 2000 patients with approximately 26% of cases receiving a molecular diagnosis. Therefore, the Baylor WGL is well suited to join the network by expanding our program to serve as the sequencing core. In response to the directives of the RFA, we will perform exome sequencing for probands and family members and deliver raw sequence reads and quality control metrics to the network within a two week period. Recognizing that the needs and experience of the various clinical sites may differ, we propose alternatives for additional sequence analysis and downstream interpretation of sequence results. These options include mitochondrial DNA sequencing; a first tier automated clinical interpretation with prioritization of variants, and an option for a full clinical interpretation in a consultative fashion with our ABMG-certified Whole Genome laboratory directors. In addition, we propose the option of whole genome sequencing. These options can be weighed by the Steering Committee to provide the most efficient and cost effective pathway to a molecular diagnosis for patients enrolled in this program.